Design and Development of Pd-catalyzed Aerobic N-Demethylation Strategies for the Synthesis of Noroxymorphone in Continuous Flow Mode

    Bernhard Gutmanna,b, David Cantilloa,b, Ulrich Weiglc, D Phillip Coxd, C. Oliver Kappea,b

    • a,b Institute of Chemistry, University of Graz, Nawi Graz, Heinrichstrasse 28, 8010 Graz, Austria and Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    • c Cilag AG, Hochstrasse 201, 8200 Schaffhausen, Switzerland
    • d Noramco Inc., 503 Carr Road, Suite 200, Wilmington, DE 19809, USA

    Strategies for the generation of noroxymorphone from 14-hydroxymorphinone are presented. Noroxymorphone is the key intermediate in the synthesis of various opioid antagonists, including naloxone, naltrexone and nalmefene, as well as mixed agonists-antagonists like nalbuphine. The transformation requires removal of the N-methyl group from the naturally occurring opiates and a double bond hydrogenation. The pivotal reaction step thereby is a N-methyl oxidation with colloidal palladium(0) as catalyst and pure oxygen as terminal oxidant. The reaction produces a 1,3-oxazolidine intermediate, which can be readily hydrolyzed to the corresponding secondary amine. Different reaction sequences and various phenol protection groups were explored. The most direct route consumes only H2, O2 and H2O as stoichiometric reagents and produces only H2O as by-product. Challenges inherent in gas-liquid reactions with oxygen as oxidant were addressed by developing a continuous flow process.

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